Insulin Regulates Neuronal M2 Muscarinic Receptor Function in the Ileum of Diabetic Rats

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Abstract

Acetylcholine release from cholinergic nerves in the gastrointestinal tract is limited by neuronal M2 muscarinic receptors. In diabetic animals, M2 muscarinic receptor function in the ileum is increased, leading to decreased acetylcholine release and smooth muscle contraction in response to nerve stimulation. The mechanisms responsible for increased M 2 muscarinic receptor function are unknown but may contribute to the gastrointestinal dysmotility that occurs frequently in diabetics. In this study, we investigated whether insulin modulates M2 muscarinic receptor function in the gastrointestinal tract of diabetic rats. M2 muscarinic receptor function was tested by measuring the ability of an agonist, pilocarpine, to inhibit and an antagonist, methoctramine, to potentiate electrical field stimulation (EFS)-induced contraction of ileum in vitro. Insulin administration (0.2, 0.6, and 2 U s.c. daily for 7 days) reversed the diabetes-induced increase in M2 muscarinic receptor function and restored normal contractions to EFS. Insulin had no effect on the function of postjunctional M3 muscarinic receptors, determined by measuring contractile responses to acetylcholine. These data suggest that insulin tonically inhibits neuronal M2 muscarinic receptors. Thus, loss of insulin removes this inhibition and increases M2 muscarinic receptor function leading to decreased acetylcholine release and contraction to EFS. In nondiabetic rats, there was a trend that higher insulin doses (0.6 and 2 U) increased M2 muscarinic receptor function, suggesting a bell-shaped concentration-response relationship for insulin. In conclusion, lack of insulin or excess insulin increases M2 muscarinic receptor function in rat ileum. This mechanism may contribute to decreased acetylcholine release in the gastrointestinal tract of diabetics, resulting in dysmotility.

Original languageEnglish (US)
Pages (from-to)760-766
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume308
Issue number2
DOIs
StatePublished - Feb 1 2004

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ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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